Mavissakalian 2001.
| Study characteristics | ||
| Methods |
Design: double‐blind placebo‐controlled RCT (i.e. second‐year double‐blind extension of Mavissakalian 1999 RCT) Prerandomisation phases Phase 0: single‐blind placebo run‐in (2 weeks) Phase 1: acute open‐label treatment with imipramine (24 weeks) Phase 2: continuation treatment with imipramine (52 weeks) (results reported in Mavissakalian 1999); remitters entered this study and were randomised to imipramine or to placebo Duration post randomisation: 52 weeks Aim: to further explore the protective effects of long‐term maintenance imipramine therapy for panic disorder in patients who survived, in stable remission, in the 1‐year maintenance discontinuation study |
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| Participants |
Country: USA Setting: community adults (outpatients from Phobia and Anxiety Disorders Clinic, clinical referrals, or in response to media coverage or advertisement) Type of antidepressant: imipramine Duration of antidepressant treatment prerandomisation: 76 weeks Duration of antidepressant post stabilisation: 52 weeks Number of participants: 110 entered phase 1, 59 in stable remission after phase 1, 56 entered phase 2, 30 completed in stable remission phase 2 Total number of randomised participants: 11 (7 placebo, 4 imipramine); 7 continued placebo and were not relevant for this review Primary diagnosis: panic disorder with agoraphobia Severity of anxiety symptoms at randomisation, mean (SD) GAS: 1.53 (0.51); self‐rating severity: 1.03 (0.89); 17‐HRDS: 4.07 (3.23) Comorbidities (n): 1 or 2 concurrent anxiety disorders 26.7% Mean age, years (SD): 35.47 (8.3) Gender distribution: not reported Inclusion criteria ‐ meeting SCID‐I DSM‐III‐R diagnostic criteria for panic disorder with agoraphobia of at least moderate severity and 3 months’ duration; patients must have been experiencing active, recurrent panic attacks at the time of initial evaluation ‐ fear of panicking or losing control must have been the primary motivation for escape or avoidance behaviours ‐ those who met operationalised response criteria at both 16‐ and 24‐week assessments after 24 weeks of imipramine were entered into phase 2 of the trial. Patients who survived, in stable remission, the first 12 months of maintenance/discontinuation were entered into the second‐year extension phase (Mavissakalian 2001). Only those patients on imipramine were re‐randomised Definition of response: either ≤ 50% improvement from pretreatment scores or a cut‐off score signifying mild to absent symptoms simultaneously on 6 or all of these measures (ESF score > 6) Exclusion criteria ‐ evidence of organic mental disorders ‐ psychotic, bipolar, and obsessive‐compulsive disorders ‐ primary or current major depression with melancholia ‐ suicidal intention or score ≥ 18 on HDRS‐17, PTSD, somatisation disorder, severe personality disorder (borderline, schizotypal), and substance abuse disorder (current or in remission for < 6 months). In addition, patients had to be in good general health, had to have no contraindications for the use of imipramine because of illness or because of treatment necessary for the illness, and had to demonstrate compliance during an initial, 2‐week, single‐blind placebo run‐in |
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| Interventions |
Intervention 1: placebo (4 identical looking tablets) Tapering scheme: 25% decrements in dose each week so that dose of 0 mg was reached on the 22nd day of randomisation Intervention 2: same dose of imipramine (2.25 mg/kg/d) Co‐intervention: no additional psychological or psychiatric treatments, but if participants had problems, additional visits for supportive intervention were provided (brief 1 or 2 sessions, crisis‐type intervention) |
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| Outcomes | Relapse: based on composite index of End‐State Functioning (ESF, range 0 to 7) derived from 7 measures
Definition of worsening: ESF ≤ 4 signified at least a 33% decline in ESF and defined worsening Defnition of relapse: at which time patients exited the study, also required that worsening be accompanied by insistent requests for therapeutic action and/or that worsening still be present in a repeated confirmatory assessment 2 weeks later Survival time without relapse, worsening, exiting in months ‐ number of panic attacks (DSM‐III definition of panic attacks, 2‐week diary, monthly) ‐ depressive symptoms assessed by 17‐HDRS |
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| Notes |
COI: not reported Funding: supported by a grant from the National Institute of Mental Health |
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| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Comment: randomisation by computer random number generator Quote: “hospital pharmacist, who used computer numbers to randomly assign patients to same‐dose imipramine continuation or placebo substitution”; “those on imipramine will be randomly assigned to placebo substitution or imipramine continuation” |
| Allocation concealment (selection bias) | Low risk | Comment: pharmacist controlled randomisation Quote: “drug condition was known only by the hospital pharmacist ... reassigned following a 2:1 ratio of those on imipramine to placebo substitution or imipramine continuation"; “identical looking tablets” |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Comment: blinding of participants and key study personnel ensured; unlikely that blinding could have been broken Quote: "double‐blind"; "4 identical looking tablets daily..." |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Comment: information insufficient to permit judgement |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Comment: 3/7 placebo and 1/4 imipramine patients did not complete the study |
| Selective reporting (reporting bias) | High risk | Comment: withdrawal symptoms and adverse events are not reported; they are fundamental outcomes in drug discontinuation studies |
| Other bias | Low risk | None |